Easing anxiety with anandamide
Novel compound could be used to help treat neurological disorders.
By trying to understand how nerve cells in the brain break down a neurotransmitter, a team of US researchers has developed a novel compound that could form the basis of drugs for treating a variety of neurological disorders, such as anxiety and drug dependency.
Anandamide is a cannabinoid neurotransmitter which forms part of a neurochemical system that helps to regulate pain, mood and appetite, and is also thought to be involved in drug dependence. In the brain, anandamide is broken down as part of a two-step process, when it is transported into nerve cells and then hydrolysed by the enzyme fatty-acid amide hydrolase (FAAH).
Exactly how anandamide is transported into the nerve cells is still unknown; it had been assumed that some sort of carrier molecule was involved, but recent findings have indicated that it may be due to passive diffusion driven by FAAH. The researchers from the University of California, Irvine (UCI), and the University of Connecticut, Storrs, wanted to ascertain the precise role of FAAH in anandamide transport.
They treated mice that lacked FAAH with a compound called N-(4-hydroxyphenyl)-arachidonamide or AM404, which is known to inhibit anandamide transport into nerve cells. However, AM404 can be hydrolysed by FAAH and so the researchers developed a hydrolysis-resistant analogue of AM404, called AM1172, which also inhibited anandamide transport but didn't interact with FAAH. In tests on nerve cells, the researchers discovered that AM404 and AM1172 inhibited anandamide transport to a similar degree. These results indicate that FAAH is not involved in the transport of anandamide into nerve cells.
Because it isn't hydrolysed by FAAH, AM1172 has a higher level of efficacy than AM404 and is also more stable. It could therefore form the basis for developing drugs that increase anandamide levels in the brain. 'By helping the body's own system give the brain a boost, compounds such as AM1172 might be able to counterbalance feelings of anxiety and depression,' says Daniele Piomelli of UCI, who led the research team.
D Fegley et al,Proc. Natl. Acad. Sci. USA, 2004, 101, 8756